Adverse Outcomes in Blood and Blood Component Therapy
Henry O. Ogedegbe, Ph.D., BB(ASCP), C(ASCP)SC,
Assistant Professor
Department of Environmental Health, Molecular and Clinical Sciences,
Florida Gulf Coast University,
10501 FGCU Blvd. South,
Fort Myers, FL 33965-6565
Tel: 941-590-7486
Fax: 941-590-7474
E-mail:
Abstract
A blood transfusion is a special kind of transplantation and/or medical therapeutic intervention that carries with it great benefits and risks to the recipient. It involves the transfer of living tissue from one person to another and thus a recipient of a transfusion may experience an adverse reaction to the product during or soon after the transfusion. It is imperative that laboratory, nursing and clinical staff understand the different types of transfusion reactions so that they can deal with the situation when it occurs. The adverse transfusion reactions may be classified as immune mediated or non-immune mediated. The immune mediated transfusion reactions are usually due to alloantibodies formed after a previous exposure to foreign antigen through pregnancy, transfusion or transplantation and may result in a hemolytic or non-hemolytic transfusion reaction. A transfusion reaction may be immediate or delayed and when hemolysis is involved, it is usually either intravascular or extravascular. The non-hemolytic reactions include febrile non-hemolytic transfusion reactions, allergic reactions and anaphylactic reactions. Cytokines have been implicated as contributing to the febrile reaction experienced by the transfusion recipient. The cytokines may be released into the blood or blood components by contaminating leukocytes in the products. Leukocytes may also cause alloimmunization, and transmission ofinfectious diseases, transfusion-related acute lung injury, andimmunomodulation. Adverse effects of transfused cellular blood componentstherefore may depend not only on the number of residual leukocytes in the blood or bloodcomponents, but also on the timing of the leukocyte removal. Extra care must be taken to ensure that the products transfused into a patient are safe and incapable of causing adverse reactions. In spite of all the care and good intensions exercised by the laboratory, nursing and clinical staff involved with transfusion therapy, accidents still occur. Many of these accidents are clerical in nature and therefore easily preventable if standard operating procedures are adhered to.

Background
A blood transfusion may be considered a special kind of transplantation, and medical therapeutic intervention that carries with it many benefits and risks to the recipient. It involves the transfer of living tissue from one person to another. At times, a recipient of a blood or blood component transfusion may experience an adverse reaction as a result of the transfusion. Because of the risk of morbidity and mortality associated with transfusion therapy, no transfusion should be given until the decision is made that it is absolutely necessary and even then it must be done with the utmost care. The adverse and at times very severe transfusion reactions experienced by some recipients of blood and blood components therapy, have variouscauses some of which include the presence of red blood cell (RBC), leukocyte or plasma proteinantibodies in the recipient and bacterial contamination of the transfusedcomponents. Fever, rigor, and dyspnea are common manifestationsof these reactions, which may be mediated by cytokines or biological response mediators (BRMs), complement,or endotoxin. Hypotension with or without urticaria or erythemamay also be a prominent feature, and bradykinin (BK) has also been implicated as mediator.1 As little as 10 to 15 ml of incompatible blood have been shown to trigger a transfusion reaction.

To prevent these potentially life threatening events from occurring, it is imperative that the clinical, nursing and laboratory staff understand the different types of transfusion reactions and how to deal with them when they occur. Transfusion reactions may be divided into immune mediated and non-immune mediated and may be categorized as immediate or delayed. The onset of a transfusion reaction may be misleading or delayed, and therefore, its detection requires astute assessment.2 The transfusionist who is often a nurse is responsible for recognizing when a transfusion reaction has occurred. The different types of transfusion reactions that may occur include: hemolytic transfusion reactions (HTRs), transfusion associated graft-versus-host disease (TA-GVHD), hemoglobinuria, post transfusion purpura (PTT), fever, circulatory overload, thrombophlebitis, urticaria, hyperkalemia, noncardiogenic pulmonary edema, and allergic and anaphylactic reactions. The transfusionist must become conversant with the signs and symptoms of a transfusion reaction and be prepared to react quickly.3 Each blood bank and transfusion service must have a system in place for detection, reporting and evaluating suspected complications of transfusion. In the event of a suspected transfusion reaction, the individual responsible for the transfusion must notify the ordering physician and the transfusion service immediately. Every transfusion reaction must be investigated promptly and the transfusion must not resume until the investigation is complete. Measures should be taken to to minimize harm to the patient.

The rate of fatal transfusion event is estimated to be about one per million units transfused but the rate of adverse reaction to transfusion of blood or blood component is estimated to be about 1 in every 200 transfusions.4 Causes of fatal transfusions reaction include misidentification of patient, mislabeling of blood sample, error in laboratory records, mistakes in blood typing, and incorrect antibody screening or crossmatching.4Typical causes of transfusion associated deaths include acute hemolysis due to ABO incompatibility, acute pulmonary edema, bacterial contamination of product, delayed transfusion reactions, anaphylaxis, external hemolysis, and graft versus host disease (GVHD).2 In vivo hemolysis of red blood cell injured by immune processes may be intravascular or extravascular. ABO antibodies are very efficient in fixing complement following sensitization of incompatible cells and therefore may precipitate an intravascular hemolytic crisis. Other antibodies such as those of Kidd, Vel Tja and Lea are also very efficient at complement fixing and may likewise cause intravascular hemolysis. Activation of complement results in the release of complement components such as C3a and C5a which act on mast cells resulting in the production of vasoactive substances such as serotonin, and histamine which mediate clinical signs and symptoms of transfusion reactions.5 When the complement cascade proceed to completion, the membrane attack complex is formed which leads to the lysis of the red blood cells.

Antigen-antibody complexes can also activate factor XII, which acts on the kinin system.1 The resultant production of bradykinin increases capillary permeability, which causes the dilation of arterioles and leads to hypotension. Hypotension activates the sympathetic nervous system with the production of catecholamines, which result in vasoconstriction in the kidney. Factor XII and thromboplastic substances produced by lysed cells activate the intrinsic clotting system, which may precipitate disseminated intravascular coagulation (DIC). This may cause the formation of thrombi, which may lodge in the lungs, liver, and kidneys. This leads eventually to the consumption of coagulation factors, production of fibrin degradation products and uncontrolled hemorrhage and renal ischemia.1,5 Extravascular hemolysis results in red blood cell removal from the circulation and destruction by cells of the reticuloendothelial system in the liver and spleen. Antibodies commonly implicated in extravascular hemolysis include anti-Jka, anti-Fya and anti-K. Extravascular hemolysis is a less severe hemolytic crisis compared to intravascular hemolysis because complement activation is not complete and the sensitized cells are gradually removed from the circulation as they circulate through the liver and the spleen.

Immediate Hemolytic Transfusion Reactions
Immediate hemolytic transfusion reactions (IHTR) occur soon after the transfusion of incompatible red blood cells. The transfused red cells are rapidly destroyed with the release of hemoglobin and stroma from the hemolyzed cells into the circulation. The cause of the hemolysis is usually due to the presence of preformed alloantibodies produced as a result of previous transfusion or pregnancy. More commonly, they are due to naturally occurring ABO antibodies. When incompatible red blood cells are transfused, antigen-antibody complexes are formed, which activate the complement, plasminogen, kinin and coagulation systems. Only a little amount of incompatible blood needs to be transfused to trigger the signs and symptoms of an impending IHTR. The first signs and symptoms may include fever, chills, general uneasiness, back pain, hemoglobinuria, dyspnea, hypotension, shock, uncontrollable bleeding, pain at the infusion site, nausea, flushing, lightheadness, substernal pain, hemoglobinemia and anemia. These reactions are the consequences of the various cytokines which are released including interleukin 1 (IL-1), tumor necrosis factor alpha (TNF-) and IL-6 and IL-8.6 These BMRs are all critical mediators of immune and inflammatory response and synergize with each other to precipitate the reactions and produce the major signs and symptoms of IHTR.

Many studies have expanded our knowledge of the pathophysiology of shock, inflammation and DIC, as they affect the outcome of HTRs. Rakic6 has shown in models of acute immunoglobulin M (IgM) mediated red cell incompatibility in experimental HTRs, that plasma TNF- levels rise sharply in a dose and time-dependent manner, peaking at 2 hours after the onset of the event. He also showed that the elevated rise in TNF- contributes to hyotension, fever, capillary permeability, and acute shock, which are associated with the HTRs. According to him, the levels of IL-8, monocyte chemotactic protein-1 (MCP-1), and neutrophil activators also rise after about 4 hours and remain elevated even after 48 hours. When the HTRs is IgG mediated, the concentrations of IL-1, IL-6, and IL-8 increase significantly within 6 hours, remain elevated for 24 hours and precipitate fever, hypotension, leukocytosis, shock, T cell proliferation and stimulation of immunoglobulin production. Increased BMRs also contribute to hemostatic dysfunction and precipitate a DIC. This may be attributed to the actions of IL-1 and TNF-, which produce changes in the hemostatic properties of endothelial cells surface, resulting in elevated tissue factor and a decrease in thrombomodulin expression and a suppression of the activity of protein C. Activation of thrombin, bradykinin, epinephrine and IL-1 may induce acute renal failure, leading to renal hypoperfusion and widespread fibrin deposit. Thus the cytokines are major contributors to the immune and inflammatory response from HTRs.6

The morbidity and mortality of an acute hemolytic transfusion reaction correlates with the amount of blood transfused. The signs and symptoms associated with extravascular IHTR are relatively mild compared to intravascular hemolysis and not as life threatening. In either type of hemolytic crisis, the patients must be provided with the care and support they need to prevent or reduce the risk of developing DIC, hypotension, and acute renal failure. The best treatment for IHTR is preventative. Most cases of IHTR are preventable because they are usually attributable to clerical errors. Error is ubiquitous whenever humans are involved in a process. Fortunately, most transfusion-related errors are benign however, the risk of death due to IHTR rivals that of HIV transmission and administration of the wrong blood or of blood component to the wrong recipient has occurred at many facilities.7 Most blood misadministration errors are caused by failure to identify the recipient and blood unit adequately, although phlebotomy errors and blood bank errors also contribute significantly. Many of the errors are multifactorial and may reflect underlying systems defects. Noncompliant specimen labels may be a cue to an increased risk of phlebotomy error. Autologous blood is not immune from error and poses infectious disease risks as well as the risk of hemolytic transfusion reaction as is perioperatively recovered blood which may pose a risk of air embolism if improperly handled.7

When all standard operating procedures (SOPs) are scrupulously followed and adhered to, to ensure proper patient identification, sample collection, labeling and identification of units, patient testing, and handling and correct transfusion at patient bedside, then the incidences of IHTR is minimized.2 Hemolytic transfusion reaction is considered a rare complication of platelet transfusion. If minor ABO incompatibility exists such as the presence of donor antibody directed against recipient's red cells in plasma-incompatible platelets, the antibodies present in the plasma of platelets might cause acute hemolysis.8

Delayed Hemolytic Transfusion Reaction
Delayed hemolytic transfusion reaction (DHTR) is the destructionof transfused blood or blood components after an interval during whichthe recipient mounts a secondary immune response to the foreignantigens. This reaction might be seen along with delayed serologic transfusion reaction(DSTR) in which transfused red cells are sensitized by newly formedantibodies without clinical hemolysis. Various alloantibodies have been implicated as causing DHTR. Rothman et al9,described a patient who developed a DHTR 11 days after receiving a transfusion, that was caused by anti-U. The case was a good illustration of the difficulty that can occur in differentiating a delayedtransfusionreaction from autoimmune hemolytic disease when the antibody involved isdirected against a high incidence blood group antigen.9 In another case, Moheng et al10, described the case of a 27-year-old, gravida 3, para 2 woman who experienced a DHTR caused by anti-Dob. She had anti-Dob in both her serum and eluate 8 daysafter transfusion of 6 units of Dob positive red cells. No antibody had beendetected prior to transfusion however, by the 15th day posttransfusion, there wasno evidence of survival of red cells from any of the 6 units. Anti-Dob are IgG, red cell stimulated antibodies that react primarily in indirect antiglobulin test (IAT) with polyethylene glycol (PEG) or enzyme enhancement.2 Anti-C andanti-M were also demonstrated later, but 29 months after transfusion, noatypical antibodies were detectable. This evidence suggests that anti-Dob shouldbe considered an antibody of potential clinical significance until contraryevidence becomes available.10

Squires et al11, described a DHTR that was precipitated by anti-Cob in a multiple transfused primigravida woman with sickle-celldisease. Sixteen days after the prophylactic transfusion of the first of 4units of red cells, the patient was reported to have experienced a fall in hemoglobin concentrationaccompanied by a newly positive antibody screen and direct antiglobulintest (DAT). Anti-Cob was identified both in her serum and in an eluateprepared from her red cells.11 Anti-Cob is encountered rarely but they is IgG, red cell stimulated and reactive in IAT. It binds complement weakly and has been known to cause DHTR. Anti-M has also been shown to cause DHTR, as was the case reported by Alperin et al.12,of a 52-year-old gravida 1, para 1 woman with M- red cells who experienced aDHTR and exhibited an anti-M antibodyfollowing the infusion of four units of M+ red cells. Measurements oferythrocyte survival using 51Cr-labeled donor M+ and M- red cells and invitro studies of monocyte-macrophage phagocytosis of sensitized reagent redcells implicate anti-M in the pathogenesis of the hemolysis.12 Chandeysson et al13,reported the case of a 67-year-old white woman who received a total of 87 units ofwhole blood and red blood cells transfusions during and within 48 hours following apneumonectomy. Even though she had previously been transfused,unexpected antibodies were not detectable by routine screening. On thesecond postoperative day, she is said to have developed fever, hemoglobinemia,hemoglobinuria, and oliguria. However, the DAT and theantibody screen were negative. On the eighth postoperative day, an IgManti-P1 antibody was detected for the first time. This anti-P1 antibodyis reported to have increased in thermal amplitude from 22 to 37 C, but remained IgM. Thecirculating transfused P1-positive cells decreased progressively withoutevidence of bleeding. Testing of the patient's preoperative blood at 15 Cfound her serum to be weakly reactive with P1 cells, while her own cellswere P2. Thus, an anamnestic response to the P1 antigen was most probably responsible for her DHTR.13 A 39-year-old multiparous woman who developed a mixed field positive DAT within 15 days of receiving four units of crossmatchcompatible red blood cells was described by Waheed et al14 as later demonstrating anti-Jsb in both her serum andan eluate prepared from her red cells. The case was complicated by the fact that the patient'spretransfusion red blood cells typed as Jsb positive. Serologic studiesdemonstrated that this was a case of allo-anti-Jsb in a Jsb positive patient,which provides evidence of heterogeniety of the Js locus.14

Garraty et al15reported the case of a 92-year-old group A, Rh-negative man with diverticulitis who wasmistyped as group AB with the use of a monoclonal anti-B reagent. Anti-B was not detected in the patient's serum and after a negative antibody screenblood was issued through an immediate-spincrossmatch. The patient received 3 units of group AB blood and 1 unit ofgroup A blood and no problems were noted. After a fourth unit of AB blood was transfused, the patient had a severe HTR, which resulted in kidney failure and death 10 days later. Afterthe transfusionreaction, the patient's pretransfusion red cells were discovered to be group A with an acquired B antigen. A sample of the patient's serumtaken before the transfusion was later found to contain a weak anti-B,detectable most obviously by the antiglobulin test, which was not performedat the crossmatch stage.15